1. Field of the Invention
The present invention is generally directed to immunoglobulin (Ig) compositions and methods of therapeutically using Ig compositions in animals including humans, livestock and domesticated animals. Several embodiments of the invention are directed to unique and novel methods of using Ig compositions in the treatment of certain maladies or conditions. These methods include the use of an Ig composition for treating stress induced respiratory disorders, diarrhea such as diarrhea caused by Parvovirus in canines, and epithelial tissue disorders including non-specific skin lesions, lymphoid hyperplasia and guttural pouch infections. Another embodiment of the invention is directed to a method for using Ig compositions to enhance weight gain in livestock. Yet a further embodiment is directed to new techniques for administering Ig compositions which are more convenient and/or more effective for a particular purpose.
The present invention is also directed to an improved Ig composition and method of making the same. The inventive composition is a sterile plasma product comprising a wide range of immunoglobulins (antibodies), and other immune constituents obtained from whole blood including complement and transfer factors extracted from white blood cells. This improved composition may be used in the novel methods of treatment described above, as well as for other applications known in the art including for use in providing passive immunity, treating auto-immune diseases, and treating various bacterial, fungal, and viral infections.
2. Description of the Related Art
It is known in the art that passive immunity may be imparted to an immune deficient patient by administering to the patient immunoglobulins (Ig) and other immune factors obtained from a donor having known immunity. For example, mother""s milk includes a composition known as colostrum which provides the newborn with immunoglobulins and other immune factors to protect it from disease until the newborn""s own immune system is more fully developed. Drawing from nature""s example, filtered plasma or serum derived from collected whole blood and containing immune factors has been utilized to convey passive immunity to patients suffering from hypogammaglobulinemia or failure of passive transfer. Intravenous (IV) or intramuscular (IM) therapy has also been used either alone or in combination with antibiotics for treating specific bacterial, fungal or viral infections, and reportedly has therapeutic effects in patients having autoimmune diseases. Thus Ig containing serums have been administered intramuscularly and intravenously for treating patients who are classified as xe2x80x9cimmune challengedxe2x80x9d in some manner. While these prior methods of treatment and administration are of great importance in the field, there remains a need to improve upon the quality and effectiveness of these methods and to expand upon the types of applications for which Ig compositions may be used. In addition, there is a need to improve upon the methods of administration so as to enhance the convenience and effectiveness of the compositions.
A particularly useful Ig composition and method of making the same was disclosed by the present inventor in U.S. Ser. No. 08/349,010 filed Dec. 2, 1994, and issuing as U.S. Pat. No. 5,548,066, which is fully incorporated herein by reference (the xe2x80x9c""010 methodxe2x80x9d). In the ""010 method, the immunoglobulin composition is prepared from whole blood collected from donors having known immunity to one or more antigens. The drawn blood is allowed to clot such that the cellular material and clotting factors (erythrocytes, lymphocytes, platelets, fibrin, etc.) are separated from the serum portion of the blood. During this clotting process some of the white blood cells rupture such that xe2x80x9ctransfer factorsxe2x80x9d and other constituents of the white blood cells spill into the serum. The serum is then separated from the clotted cells and filtered to remove all of the cellular fragments, thereby producing a serum product. This filtered serum product may then be concentrated via removal of water and other low molecular weight substances. The concentrated serum is then sterilized, but not denatured, by a novel method of freezing the serum and subjecting it to specified doses of gamma irradiation while frozen. Once sterilized, the serum can be thawed and stored as a liquid under refrigeration conditions for several months.
The resulting composition of the ""010 method comprises a sterile and concentrated serum having a wide range of immunoglobulins or antibodies and other immune constituents such as the xe2x80x9ctransfer factorsxe2x80x9d expressed from the white blood cells. The ""010 preparation is particularly useful for immunotherapy insofar as the serum is readily available to the user in a convenient purified and liquid refrigerated form. In the past, commercial plasma used for immunotherapy (particularly by ranchers in treating livestock) was required to be kept frozen requiring the user to thaw and filter the plasma just before use. The ""010 composition in contrast is immediately ready for use. The ""010 composition is also advantageous in that it can be used for oral administration, in addition to conventional intravenous injection. Oral administration is preferred in certain circumstances because the immunoglobulins may be more readily absorbed and distributed within the patient. Furthermore, oral administration is more convenient and safer than intravenous applications which require careful control and monitoring of drip rate.
While the ""010 composition has many advantages over compositions of the prior art, the technique of clotting the blood to separate the cellular and serum fractions has some drawbacks. In particular, insofar as complement in the blood is thermolabile, a certain amount of complement may be degraded ova time while the blood is allowed to clot. Furthermore, it is believed that white blood cells may become trapped within the red blood cells during the clotting process such that a portion of these cells remain intact and do not expel transfer factors into the serum. For this reason, the total amount of complement and transfer factors available in the collected blood is not expressed in the final product.
It is therefore an object of the present invention to provide new methods of using and administering immunoglobulin compositions for therapeutic and/or livestock management purposes.
Another object of the invention is to provide an improved immunoglobulin composition and method of making the same.
These and other objects are achieved by several methods discovered by the inventor of using immunoglobulin (Ig) preparations for therapeutic and/or livestock management purposes.
Of particular import, the inventor has discovered a novel method of enhancing weight gain in patients, particularly cattle and other livestock, wherein the method comprises administering one or more doses of an immunoglobulin composition to the animal. In this method, the Ig composition may be administered in any conventional manner or is preferably administered via a novel method of subcutaneous injection which is particularly convenient and effective for this purpose.
The inventor has also discovered a method of preventing and/or treating stress induced respiratory disorders including bovine and porcine respiratory disease complex, upper respiratory infections in horses and exercise induced pulmonary hemorrhage. In this method, one or more doses of an immunoglobulin composition is administered to the animal preferably immediately before or after the stressful occurrence. While any conventional mode of administration is deemed suitable, the inventor has found that for purposes of treating livestock such as cattle, the novel method of subcutaneous injection is preferred. For purposes of treating horses, direct application to the lungs via intratracheal injection or vapor inhalation is preferred.
Yet another method developed by the inventor is a novel method of treating diarrhea including diarrhea caused by Parvovirus in canines. This method comprises administering an immunoglobulin composition to the patient in any conventional manner with oral and/or subcutaneous administration being most preferred.
The inventor has also discovered methods for treating epithelial tissue disorders such as non-specific skin lesions, lymphoid hyperplasia and guttural pouch infections. This method comprises administering one or more doses of an Ig preparation to the patient suffering from the disorder. In these methods, the Ig preparation may be administered in any conventional manner but is particularly useful if administered via novel modes of subcutaneous injection or direct application to the affected tissue.
In another embodiment of the invention, the inventor has developed an improved Ig composition and method of making the same whereby the composition is prepared from whole blood without permitting the blood to clot before extraction. It is believed that this improved method increases the overall amount of immunoglobulins, complement, transfer factors and other immune constituents extracted from the whole blood. The improved method includes the steps of collecting whole blood from one or more donors, wherein the donors have known immunity for a variety of ailments. An anti-coagulant such as citrate-phosphate-dextrose (CPD) is then mixed with the collected blood in sufficient amount to prevent the blood from clotting. The anti-coagulant and whole blood mixture is then allowed to stand undisturbed until the red blood cells contained within the blood settle to the bottom of the collection vessel forming a bottom red blood cell layer. The white blood cells and liquid plasma form middle and upper layers respectively. In some species, it may be necessary to subject the anti-coagulant and whole blood mixture to centrifugation in order to obtain this layered separation.
Upon separation, the plasma and white blood cell layers are immediately separated from the red blood cell layer and preferably chilled. The white blood cells and plasma are then subjected to one or more filtration steps whereby at least a portion of the white blood cells are ruptured so that transfer factors contained within the white blood cells spill into the liquid plasma. The cellular fragments do not pass through the filter such that the resulting filtered plasma substantially comprises a liquid. Optionally, the filtered plasma may be concentrated to remove water and other low molecular weight components. The filtered and/or concentrated plasma is then sterilized preferably by freezing the plasma and irradiating the plasma while in the frozen state. The sterilized plasma may then be allowed to thaw and to be stored in a liquid state under refrigerated conditions.